Table 1. Screening of the Solvent and Reaction Conditions for
the Double Michael Reactiona
Scheme 1. Retrosynthetic Analysis
entry
solvent
temp (°C)
time (h)
yieldb(%)
drc
R-alkyl-R,β-unsaturated aldehydes have usually involved
strong nucleophiles such as indoles,5 nitromethane,6 or
NHC catalysis.7 Alternative asymmetric metal-catalyzed
strategies for the conjugate addition to R-alkyl-R,β-unsatu-
rated aldehydes have also been lacking and remain a compel-
ling area of investigation.8
In an effort to extend our earlier studies on organocata-
lyzed annulations9,10 and to merge photoredox catalysis
and organocatalysis,11 we envisioned a cascade of organo-
catalytic double Michael and photoredox catalyzed
Michaelꢀaldol reactions12 involving ethyl 2-bromo-6-
formylhex-2-enoate, β-alkyl-R,β-unsaturated aldehydes,
1
CH2Cl2
MeCN
H2O
28
28
24
0
16
5
66
69
56
82
87
78
50
9.4:1
7.1:1
5.4:1
9.0:1
13.6:1
2.4:1
4.2:1
2d
3e
4
1
CH2Cl2
MeCN
EtOHf
toluene
16
17
20
49
5
0
6
0
7
0
a Unless otherwise noted, the reactions were performed with cat.
IꢀHOAc (20 mol %) in 0.1 M of 1 with a ratio 1.5/1 of 2a/1. b Isolated
yield. c Determined by the 1H NMR of the crude product. d Reaction
proceeded with30 mol % of catalyst;the reactionwithless catalyst gavean
incomplete reaction. e Reaction with a ratio of 6/1 of 2a/1. f 99% EtOH.
and R-alkyl-R,β-unsaturated aldehydes that might provide
a useful protocol for the formation of the highly functio-
nalized decaline system containing multiple contiguous
stereogenic centers and bearing a quaternary stereocenter,
as illustrated in Scheme 1.
(4) (a) Quintard, A.; Lefranc, A.; Alexakis, A. Org. Lett. 2011, 13,
1540. (b) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Soc. Chem. 2003, 125,
9022.
(5) (a) Galzerano, P.; Pesciaioli, F.; Mazzanti, A.; Bartoli, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7892. (b) Fu, N.; Zhang,
L.; Li, J.; Luo, S.; Cheng, J.-P. Angew. Chem., Int. Ed. 2011, 50, 11451.
(c) King, H. D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura, R.; Wu,
D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437.
(6) (a) Guo, L.; Zhang, W.; Guzei, I. A.; Spencer, L. C.; Gellman,
S. H. Org. Lett. 2012, 14, 2582. (b) Malihi, F.; Clive, D. L. J.; Chang,
C.-C. J. Org. Chem. 2013, 78, 996.
(7) (a) Singh, A. K.; Chawla, R.; Rai, A.; Yadav, L. D. S. Chem.
Commun. 2012, 48, 3766. (b) Kravina, A. G.; Mahatthananchai, J.;
Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 9433.
At the outset of the study, the reaction of 1 with1.5 equiv
of cinnamaldehyde (2a) in the presence of the Jørgensenꢀ
Hayashi catalyst IꢀAcOH (20 mol %)13 in CH2Cl2 at
ambient temperature for 16 h afforded a 66% yield of the
expected double Michael adduct 3a with a 9.4:1 ratio of
diastereomers, arising from the CHꢀBr center (Table 1,
entry 1). Perhaps due to the rapid consumption of the
catalyst in the CH3CN media, the reaction with 20 mol %
of catalyst IꢀAcOH in CH3CN at ambient temperature
was haltedafter 9 h and even after 2 days was not complete.
Byincreasingthecatalystloading to 30mol %, the reaction
in CH3CN was completed in 5 h and gave a 69% yield of 3a
with 7.1:1 dr (Table 1, entry 2). The reaction in aqueous
media with an excess of 2a (6 equiv) was facilitated and
was completed in 1 h, but afforded a lesser yield of 3a with
less selectivity, 56% yield, 5.4:1 dr (Table 1, entry 3).
Subsequently, the reaction at a lower temperature (0 °C)
gave higher yields and better diastereoselectivity (Table 1,
entries 4 and 5). The best conditions for this reaction were
obtained in CH3CN for 17 h to give an 87% yield of 3a with
13.6 dr. The reactions in other solvents (e.g., EtOH, toluene),
however, afforded lower yields of 3a (entries 6ꢀ7).
(8) Clive, D. L. J.; Liu, D. Angew. Chem., Int. Ed. 2007, 46, 3738.
(9) For a recent review in organocatalyzed cycloadditions, see: Hong,
B.-C. Organocatalyzed Cycloadditions. In Enantioselective Organoca-
talyzed Reactions II; Mahrwald, R., Ed.; Springer: Dordrecht, 2011;
Chapter 3, pp 187ꢀ244.
(10) (i) Dange, N. S.; Hong, B.-C.; Lee, C.-C.; Lee, G.-H. Org. Lett.
2013, 15, 3914. (a) Hong, B.-C.; Liao, W.-K.; Dange, N. S.; Liao, J.-H. Org.
Lett. 2013, 15, 468. (b) Hong, B.-C.; Dange, N. S.; Yen, P.-J.; G.-H. Lee,
G.-H.; Liao, J.-H. Org. Lett. 2012, 14, 5346. (c) Hong, B.-C.; Chen, P.-Y.;
Kotame, P.; Lu, P.-Y.; Lee, G.-H.; JLiao, J.-H. Chem. Commun. 2012, 48,
7790. (d) Hong, B.-C.; Dange, N. S.; Ding, C.-F.; Liao, J.-H. Org. Lett.
2012, 14, 448. (e) Hong, B.-C.; Hsu, C.-S.; Lee, G.-H. Chem. Commun. 2012,
48, 2385. (f) Hong, B.-C.; Kotame, P.; Lee, G.-H. Org. Lett. 2011, 13, 5758.
(g) Hong, B.-C.; Dange, N. S.; Hsu, C.-S.; Liao, J.-H.; Lee, G.-H.Org. Lett.
2011, 13, 1338. (h) Hong, B.-C.; Nimje, R. Y.; Lin, C.-W.; Liao, J.-H. Org.
Lett. 2011, 13, 1278 and references cited therein.
(11) For recent reviews in the merging of two types of catalytic cycles
in one pot, see: (a) Patil, N. T.; Shinde, V. S.; Gajula, B. Org. Biomol.
Chem. 2012, 10, 211. (b) Zhou, J. Chem.;Asian J. 2010, 5, 422. (c)
Wende, R. C.; Schreiner, P. R. Green Chem. 2012, 14, 1821. (d) Du, Z.;
Shao, Z. Chem. Soc. Rev. 2013, 42, 1337. (e) Loh, C. C.; Enders, D.
Chem.;Eur. J. 2012, 18, 10212. (f) Patil, N. T. Angew. Chem., Int. Ed.
2011, 50, 1759. (g) Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 16, 2999.
(h) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem.;Eur. J. 2010, 16,
9350. (i) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. For
examples, see: (j) Nicewics, D. A.; MacMillan, W. C. Science 2008, 322,
77. (k) Shih, H.-W.; Wal, M. N. V.; Grange, R. L.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2010, 132, 13600. (l) Nagib, D. A.; Scott, M. E.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875. (m)
With 3a in hand, we began our investigation employing
the photoredox catalysis by irradiating a mixture of
3a (0.03 M)14 and methacrolein (4 equiv) in the presence
of catalytic amounts of Ru(bpy)3(BF4)2 (5 mol %) and
€
€
Neumann, M.; Fuldner, S.; Konig, B.; Zeitler, K. Angew. Chem., Int.
Ed. 2011, 50, 951. (n) Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.;
MacMillan, D. W. C. Science 2013, 339, 1593. (o) DiRocco, D. A.;
Rovis, T. J. Am. Chem. Soc. 2012, 134, 8094.
(13) A series of organocatalysts were screened, and the conditions with
catalyst IꢀAcOH were found to be the best. For previous studies in the
organocatalytic domino double Michael reaction of ethyl (E)-7-oxohept-2-
enoate and R,β-unsaturated aldehydes, see: (a) Hong, B.-C.; Liao, W.-K.;
Dange, N. S.; Liao, J.-H. Org. Lett. 2013, 15, 468. (b) Hong, B.-C.; Sadani,
A. A.; Nimje, R. Y.; Dange, N. S.; Lee, G.-H. Synthesis 2011, 12, 1887.
(12) For an addition of the R-aminoalkyl radical to electron-deficient
alkenes by visible-light photoredox catalysts, see: Miyake, Y.; Nakajima,
K.; Nishibayashi, Y. J. Am. Chem. Soc. 2012, 134, 3338.
B
Org. Lett., Vol. XX, No. XX, XXXX